Composition and/or method for preventing onset and/or recurrence of cardiovascular events

ABSTRACT

Provided are composition and/or methods useful in preventing onset and/or recurrence of cardiovascular events, especially in patients who have escaped the unstable period after cardiovascular angioplasty or in hyperlipidemia patients who have been treated with HMG-CoA RI.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 37 C.F.R. §1.53(b) continuation of U.S.application Ser. No. 11/481,956 filed Jul. 7, 2006, which claims thebenefit of priority to Japan Patent Application No. 2005-200503, filedon Jul. 8, 2005. The contents of each of these applications isincorporated herein by reference.

TECHNICAL FIELD

This invention relates to compositions and/or methods for preventingonset and/or recurrence of cardiovascular events which contain at leastethyl icosapentate (hereinafter abbreviated as EPA-E).

BACKGROUND ART

Westernization of diet has resulted in the increase of patientssuffering from lifestyle-related diseases such as diabetes,hyperlipidemia, and hypertension. Some of these diseases finally lead toarteriosclerotic diseases such as myocardial infarction, anginapectoris, and cerebral infarction and sometimes results in death. Astreatment of arteriosclerotic diseases, for example, drugs or surgicalmethods such as vascular angioplasty are generally utilized.

For prevention of arteriosclerotic diseases or improvement of quality oflife, it is important to reduce risk factors such as hyperlipidemia,diabetes, hypertension, and smoking habits. In the major epidemiologicalsurvey where incidence rates of hyperlipidemia and coronary arterydisease were examined, positive correlation was found between serumtotal cholesterol (hereinafter abbreviated as T-Cho) concentration orserum triglyceride (hereinafter abbreviated as TG) concentration and theonset of the coronary artery disease. More specifically, even strongerpositive correlation was found for the serum low density lipoproteincholesterol (hereinafter abbreviated as LDL-Cho) concentration, whilenegative correlation was found for the serum high density lipoproteincholesterol (hereinafter abbreviated as HDL-Cho) concentration.

Pharmacotherapy of hyperlipidemia has become relatively easy, andsuppression of onset of coronary artery diseases by a strong therapy ofhyperlipidemia using 3-hydroxy-3-methylglutaryl coenzyme A reductaseinhibitor (hereinafter abbreviated as HMG-CoA RI) has been proven in alarge scale clinical trial. For example, when male hyperlipidemiapatients with no history of myocardial infarction were orallyadministered with pravastatin sodium for an average period of 4.9 years,serum T-Cho concentration decreased by 20%, serum LDL-Cho concentrationdecreased by 26%, serum HDL-Cho concentration increased by 5%, and serumTG decreased by 12%, and as a consequence, the total incidence rate ofnonfatal myocardial infarction and cardiovascular death decreased by 31%(The New England Journal of the Medicine, 1995, vol. 333, pp.1301-1307). When patients with history of angina pectoris or myocardialinfarction were orally administered with simvastatin for an averageperiod of 5.4 years, serum T-Cho concentration decreased by 25%, andserum LDL-Cho concentration decreased by 35%, serum HDL-Choconcentration increased by 8%, and serum TG decreased by 10%, and as aconsequence, the incidence rate of major cardiovascular events decreasedby 34% (The Lancet, 1994, vol. 344, pp. 1383-1389). The decrease in theincidence rate of the cardiovascular events was also approximately 20 to30% in other large scale clinical trials using HMG-CoA RI (Archives ofInternal Medicine, 1999, vol. 159, No. 1, pp. 1793-1802). These resultsmay not be sufficient for clinical practice.

It has been reported that when a capsule that includes a ω-3polyunsaturated fatty acid composition containing EPA-E and ethyldocosahexaenoate (hereinafter abbreviated as DHA-E) in a total amount of850 to 882 mg was orally administered to patients within three monthsfrom the onset of acute myocardial infarction every day for 3.5 years,the combined incidence rate of cardiovascular death, nonfatal myocardialinfarction, and nonfatal cerebral infarction decreased by 20%, and that,while cardiovascular death decreased by 30%, no significant effect wasobserved on nonfatal cardiovascular events (The Lancet, vol. 354, Aug.7, 1999, pp. 447-455). It was also reported that their death ratedecreased when 1 g of essential fatty acids containing EPA-E and DHA-Ein a total amount of 85% was administered to patients with history ofmyocardial infarction every day for 3.5 years (WO 00/48592 (JP2002-537252 A)). It is also disclosed that the use of EPA or DHA incombination with a cholesterol synthesis inhibitor repressescardiovascular events (U.S. Pat. No. 6,159,993).

High purity EPA-E is commercially available in the trade names of Epadeland Epadel S (manufactured by Mochida Pharmaceutical Co., Ltd.) as thetherapeutic drug for hyperlipidemia. It has been reported that when suchhigh purity EPA-E is orally administered at 600 mg per administrationand three times a day immediately after meals (when serum TG isabnormal, the dose can be increased to the level of 900 mg peradministration and three times a day), serum T-Cho concentration andserum TG can be reduced by 3 to 6% and by 14 to 20%, respectively (DrugInterview Form “EPA preparation, Epadel capsule 300,” revised in July,2002; January, 2003; pp. 21-22.), and that based on such action, suchhigh purity EPA-E is expected to exert effects on cardiovascular eventsof hyperlipidemia patients (American Heart Journal, 2003, vol. 146, No.4, pp. 613-620).

On the other hand, as an option for treatment of Ischemic heart disease,a surgical treatment, cardiovascular angioplasty such as PTCA, andcoronary stent implantation has been widely carried out mainly forserious patients, but cardiovascular events are easy to occur after theangioplasty. For example, the cardiovascular event after PTCA is due torestenosis at the PTCA site, which generally means progression ofstenosis in more than 50% of the region expanded by PTCA, or generationof new lesion in many cases. The restenosis rate is approximately 30-40%and the restenosis is usually observed at or within six months. Therestenosis rate can be reduced by using stent but it is not alwaysreliable (T. Yamaguchi & M. Kitahara, Kon-nichi no tiryoushishin,published by IGAKUSHOIN, pp. 237, 2003).

As medical treatment with drugs after cardiovascular angioplasty,anti-platelet agents are often used. F or example, a combination ofaspirin and Ticlopidine (Clopidogrel) is administered as a matter ofcourse when a stent is inserted. For prevention of stent thrombi, acombination of aspirin and cilostazol is administered (T. Yamaguchi & M.Kitahara, Kon-nichi no tiryoushishin, published by IGAKUSHOIN, pp.245-246, 2003). In particular, care after the surgery is consideredimportant.

Although fish oil or omega-3 fatty acids have been administered to thepatients with restenosis in the unstable period after cardiovascularangioplasty, there are controversial reports regarding their efficacy,while there is a view that they have to start to be administered beforethe cardiovascular angioplasty (J. Am. Coll. Cardiol. 2005 May17;45(10):1723-8; Am. Heart J. 2002 Jun; 143(6):E5; J. Am. Coll.Cardiol. 1999 May; 33(6):1619-26; Am. J. Cardiol. 77, 31-36 (1996)).

Although it was reported that two-year administration of HMG-CoA RI,plavastatin, after PTCA had reduced the restenosis rate and thus beeneffective for repression of the cardiovascular events (Am. J. Cardiol.2000 Oct. 1; 86(7):742-6) as well as that three- to four-yearadministration of fluvastatin from immediately after PercutaneousCoronary Artery intervention repressed the onset of the cardiovascularevents (JAMA, 2002 Jun 26; 287(24):3215-22), an improved treatment isexpected, which enable more repression of the cardiovascular events.

SUMMARY OF THE INVENTION

In view of the situation that death from the cardiovascular diseases isstill a major cause of death, and it is a serious problem that manycardiovascular events are still impossible to prevent by the HMG-CoA RItherapy, an object of the present invention is to provide a compositionand/or method for preventing onset and/or recurrence of thecardiovascular events.

In order to solve the problems described above, the inventors of thepresent invention made an extensive study and found that EPA-E has aneffect of preventing onset and/or recurrence of the cardiovascularevents, and in particular, an effect of preventing onset and/orrecurrence of the cardiovascular events in patients who have escaped theunstable period after cardiovascular angioplasty. The present inventionhas been thus completed on the basis of such findings. Accordingly, thepresent invention is directed to:

(1) composition for preventing onset and/or recurrence of cardiovascularevents comprising at least EPA-E as its effective component;specifically,(2) composition for preventing onset and/or recurrence of cardiovascularevents in a hyperlipidemia patient to whom HMG-CoA RI treatment has beencarried out, comprising administrating to the patient the compositioncontaining ethyl icosapentate as its effective component;(3) method for preventing onset and/or recurrence of cardiovascularevents in a patient who has history of acute myocardial infarction,comprising administrating to the patient the composition containingethyl icosapentate as its effective component;(4) method for preventing onset and/or recurrence of cardiovascularevents in a patient who has escaped the unstable period aftercardiovascular angioplasty, comprising administrating to the patient thecomposition containing ethyl icosapentate as its effective component;(5) method according to (4), in which the composition starts to beadministered after the patient has escaped the unstable period;(6) method for preventing onset and/or recurrence of cardiovascularevents in a patient beyond six months after the cardiovascularangioplasty, comprising administrating to the patient the compositioncontaining ethyl icosapentate as its effective component;(7) method according to any of (4) to (6), in which the administrationof the composition is started beyond six months after the cardiovascularangioplasty and is continued at least for two years;(8) method according to any of (4) to (7), in which the cardiovascularangioplasty is selected from a group consisting of percutaneoustransluminal coronary angioplasty (PTCA), percutaneous transluminalcoronary recanalization (PTCR), directional coronary atherectomy (DCA),coronary stent implantation (coronary artery stenting), and coronaryartery bypass grafting (AC bypass grafting);(9) method according to any of (1) to (8), in which the patient suffersfrom hyperlipidemia;(10) method according to any of (1) to (9), in which the proportion ofthe ethyl icosapentate in the total content of fatty acids andderivatives thereof is 96.5% by weight or more;(11) method according to any of (1) to (10), in which the ethylicosapentate is orally administered at an amount of 0.3 g/day to 6.0g/day immediately after meals;(12) method according to any of (1) to (11), in which the composition isused in combination with an inhibitor for 3-hydroxy-3-methylglutarylcoenzyme A reductase;(13) method according to (12), in which the inhibitor is pravastatin orsimvastatin; and(14) method according to any of (1) to (13), further comprising DHA-E.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Next, the present invention is described in detail.

A first embodiment of the present invention is a composition and/or amethod for preventing onset and/or recurrence of the cardiovascularevents which contains EPA-E as its effective component.

Although any composition for prevention of any onset and/or recurrenceof cardiovascular events at least containing EPA-E as its effectivecomponent is within the scope of this invention, preferred examplesinclude compositions for prevention of cardiovascular death, fatalmyocardial infarction, sudden cardiac death, nonfatal myocardialinfarction, cardiovascular angioplasty, new onset of rest angina andeffort angina, and destabilization of angina pectoris. The subject ofthe administration of the composition includes all humans requiringprevention of onset of cardiovascular events, and preferred examplesinclude hyperlipidemia patients. While EPA-E content in the total fattyacid and dosage of administration are not particularly limited as longas intended effects of the present invention are attained, high purityEPA-E is preferred; for example, the composition having a proportion ofthe EPA-E of preferably 40% by weight or more, more preferably 90% byweight or more, and still more preferably 96.5% by weight or more intotal of the fatty acids and their derivatives. The daily amount interms of EPA-E is typically 0.3 to 6.0 g/day. preferably 0.9 to 3.6g/day, and still more preferably 1.8 to 2.7 g/day.

Other preferable fatty acid contained is any omega-3 unsaturated fattyacid, especially DHA-E. The ratio of EPA-E/DHA-E in the composition, thecontent of EPA-E and DHA-E in the total fatty acids and administrationamount of EPA-E and DHA-E are not limited but the ratio is preferably0.8 or more, more preferably 1.0 or more, still more preferably 1.2 ormore. The composition is preferably highly purified; for example, theproportion of EPA-E+DHA-E in the fatty acids and their derivatives ispreferably 40% by weight or more, more preferably 80% by weight or more,and still more preferably 90% or more. The daily amount in terms ofEPA-E+DHA-E is typically 0.3 to 10.0 g/day, preferably 0.5 to 6.0 g/day,and still more preferably 1.0 to 4.0 g/day. The low content of otherlong chain saturated fatty acids is preferred, and among the long chainunsaturated fatty acids, the content of ω-6 fatty acids, and inparticular, the content of arachidonic acid is preferably as low as lessthan 2% by weight, and more preferably less than 1% by weight.

A second embodiment of the present invention is a composition and/or amethod for preventing onset and/or recurrence of cardiovascular eventsof hyperlipidemia patients who is undergoing HMG-CoA RI therapy, whichcontains at least EPA-E as its effective component. While HMG-CoA RIincludes all inhibitors of 3-hydroxy-3-methylglutaryl coenzyme Areductase, a pharmaceutically administrable inhibitor is preferablyused, which is preferably pravastatin, simvastatin, lovastatin,fluvastatin, cerivastatin, atorvastatin, pitavastatin, rosuvastatin, andsalts and derivatives thereof, and more preferably, pravastatin,lovastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, orrosuvastatin, and most preferably, pravastatin or simvastatin.

All pharmaceutically administrable salts can be used, and preferred aresodium and potassium salts such as pravastatin sodium, fluvastatinsodium, cerivastatin sodium, atorvastatin calcium, pitavastatin calcium,and rosuvastatin calcium. In the present invention, “pravastatin,” forexample, also includes the pravastatin in the form of a salt unlessotherwise noted.

A third embodiment of the present invention is a composition and/or amethod for preventing onset and/or recurrence of cardiovascular eventsin patients who have history of acute myocardial infarction, whichcontains at least EPA-E as its effective component.

In the second and third embodiments of the present invention, preferredembodiments of the type of the cardiovascular events, proportion of theEPA-E in the total fatty acid, daily amount, and proportion of otherlong chain fatty acids are the same as those of the first embodiment ofthe present invention as described above.

A fourth embodiment of the present invention is a composition and/or amethod for preventing onset and/or recurrence of cardiovascular eventsin patients who have escaped the unstable period after cardiovascularangioplasty, which contains at least EPA-E as its effective component.The patients who underwent cardiovascular angioplasty have a highpossibility to show the symptoms due to the cardiovascular angioplastyitself within about six months and a higher possibility within aboutthree months, after the cardiovascular angioplasty. This period isreferred to as the unstable period in this specification. Therefore, afourth embodiment of the present invention is preferably a compositionfor preventing onset and/or recurrence of cardiovascular events inpatients beyond six months after the cardiovascular angioplasty. Thusthe cardiovascular events such as restenosis during the unstable period,which are caused by the cardiovascular angioplasty itself, are excludedfrom the scope of this invention. The type of the cardiovascularangioplasty is not particularly limited, and examples includepercutaneous transluminal coronary angioplasty (hereinafter abbreviatedas PTCA), percutaneous transluminal coronary recanalization (hereinafterabbreviated as PTCR), directional coronary atherectomy (hereinafterabbreviated as DCA), coronary stent implantation (coronary arterystenting), and coronary artery bypass grafting (hereinafter abbreviatedas AC bypass grafting).

A fifth embodiment of the present invention is a composition and/or amethod for preventing onset and/or recurrence of cardiovascular eventsin patients who have escaped the unstable period after cardiovascularangioplasty, which contains at least EPA-E as its effective component,and preferably a composition for preventing onset and/or recurrence ofcardiovascular events in patients beyond six months after thecardiovascular angioplasty.

The composition according to the fourth and fifth embodiments isadministered to the patients who have escaped the unstable period aftercardiovascular angioplasty and preferably to the patients beyond sixmonths after the cardiovascular angioplasty.

The cardiovascular events that occur after the unstable period arethought to generate by a mechanism which is different from that of thecardiovascular events such as restenosis during the unstable period,which are caused by the cardiovascular angioplasty itself. The rate ofthe cardiovascular events that occur after the unstable period isrelatively high. The composition according to the fourth and fifthembodiments is administered after the unstable period, specificallybeyond after cardiovascular angioplasty. The composition is preferableto be administered continuously for a long time, specifically for twoyears or more, more preferably for three years and a half or more, stillmore preferably for five years or more and thus is effective forpreventing onset and/or recurrence of cardiovascular events which occurafter the unstable period.

While EPA-E content in the total fatty acid and dosage of thecompositions according to the fourth and fifth embodiments of thepresent invention are not particularly limited as long as thecomposition contains EPA-E as its effective component and intendedeffects of the present invention are attained, high purity EPA-E ispreferably used; for example, the composition having a proportion of theEPA-E of preferably 40% by weight or more, more preferably 90% by weightor more, and still more preferably 96.5% by weight or more in total ofthe fatty acids and their derivatives. The daily amount in terms ofEPA-E is typically 0.3 to 6 g/day, preferably 0.9 to 3.6 g/day, andstill more preferably 1.8 to 2.7 g/day.

Other preferable fatty acid contained is any omega-3 unsaturated fattyacid, especially DHA-E. The ratio of EPA-E/DHA-E in the composition, thecontent of EPA-E and DHA-E in the total fatty acids and administrationamount of EPA-E and DHA-E are not limited but the ratio is preferably0.8 or more, more preferably 1.0 or more, still more preferably 1.2 ormore. The composition is preferably highly purified; for example, theproportion of EPA-E+DHA-E in the fatty acids and their derivatives ispreferably 40% by weight or more, more preferably 80% by weight or more,and still more preferably 90% or more. The daily amount in terms ofEPA-E+DHA-E is typically 0.3 to 10.0 g/day, preferably 0.5 to 6.0 g/day,and still more preferably 1.0 to 4.0 g/day. The low content of otherlong chain saturated fatty acids is preferred, and among the long chainunsaturated fatty acids, the content of ω-6 fatty acids, and inparticular, the content of arachidonic acid is preferably as low as lessthan 2% by weight, and more preferably less than 1% by weight.

The compositions according to the first to fifth embodiments of thepresent invention have the effect of preventing onset and/or recurrenceof cardiovascular events when orally administered to a normal person, aperson suffering from hyperlipidemia, diabetes or hypertension with therisk of cardiovascular events, or a patient to whom HMG-CoA RI treatmenthas been carried out, although those whom the compositions areadministered are not limited thereto. The composition of the presentinvention also has a combined effect when used with HMG-CoA RI, andaccordingly, onset and/or recurrence of the cardiovascular events can beeven more effectively prevented by using in combination with the HMG-CoARI.

The compositions of the present invention contain a smaller amount ofimpurities such as saturated fatty acids and arachidonic acid, which areunfavorable for cardiovascular events, than fish oil or fish oilconcentrate, and intended effects can be attained without causingproblems like over-nutrition or excessive intake of vitamin A. Inaddition, since the effective form of the present composition is anester, which is more stable to oxidation than that in fish oil in whichits effective form is a triglyceride, a sufficiently stable compositioncan be produced by adding a conventional antioxidant. Thus the use ofthe EPA-E has enabled production of a composition for preventing onsetand/or recurrence of cardiovascular events which can be used in clinicalpractice.

In the present invention, the term “icosapentaenoic acid” designatesall-cis-5,8,11,14,17-icosapentaenoic acid.

In the present invention, the term “cardiovascular events” is used togenerally refer to pathological changes of cardiovascular system, andincludes cardiovascular death (fatal myocardial infarction and suddencardiac death), nonfatal myocardial infarction, cardiovascularangioplasty (PTCA, PTCR, DCA, coronary stent implantation (coronaryartery stenting), and AC bypass grafting), new onset of rest angina oreffort angina, and destabilization of angina pectoris (hospitalization,and PTCA, PTCR, DCA, coronary stent implantation (coronary arterystenting), AC bypass grafting, or other cardiovascular angioplasty).

In the present invention, the term “hyperlipidemia patient” designatesthe patient experiencing increase in serum T-Cho concentration, increasein serum LDL-Cho concentration, decrease in serum HDL-Cho concentration,or increase in serum TG. In the narrow sense, the term “hyperlipidemiapatient” designates, a patient who suffers from any one ofhypercholesterolemia (with the serum T-Cho concentration of about 220mg/dl or higher, and in the narrower sense, with the serum T-Choconcentration of 250 mg/dl or higher), hyper-LDL cholesterolemia (withthe serum LDL-Cho concentration of 140 mg/dl or higher), hypo-HDLcholesterolemia (with the serum HDL-Cho concentration of less than 40mg/dl) and hypertriglyceridemia (with the serum TG of 150 mg/dl orhigher).

In the present invention, the term “use in combination with HMG-CoA RI”includes both the embodiment in which the composition containing EPA-Eas its effective component and the HMG-CoA RI are simultaneouslyadministered and the embodiment in which both agents are separatelyadministered. When these agents are simultaneously administered, theymay be formulated either as a combination drug, or separate drugs. Whenthese agents are separately administered, the composition containingEPA-E as its effective component may be administered either before orafter the HMG-CoA RI. The administration amount and ratio of thecomposition containing EPA-E as its effective component and the HMG-CoARI may be adequately selected. Preferable examples of use of HMG-CoA RIwhich is administered in combination is the similar to those shown inthe second embodiment as example.

The compositions and/or methods according to the first to fifthembodiments of the present invention has the action of preventing onsetand/or recurrence of the cardiovascular events by sole administration ofthe composition, and in particular, the present composition is expectedto exert an effect of preventing onset and/or recurrence of thecardiovascular events which cannot be prevented by administration of theHMG-CoA RI. In addition, EPA-E has not only the action of reducing theserum T-Cho concentration and the serum TG, but also the action ofsuppressing platelet aggregation based on inhibition of arachidonic acidcascade, which is a pharmacological action different from the HMG-CoARI. Therefore, the stronger action of preventing onset and/or recurrenceof the cardiovascular events of the present composition can be exertedby using in combination with the HMG-CoA RI.

The compositions according to the first to fifth embodiments of thepresent invention can include pharmaceutically accepted carriers as wellas its effective component. Since EPA-E and DHA-E are highlyunsaturated, inclusion of an effective amount of an antioxidant such asbutylated hydroxytoluene, butylated hydroxyanisole, propyl gallate,gallic acid, and pharmaceutically acceptable quinone, and α-tocopherolis preferable.

The preparation may be orally administered to the patients in the dosageform of tablet, capsule, microcapsule, granules, fine granules, powder,oral liquid preparation, syrup, or jelly. Preferably, the preparation isfilled in a capsule such as soft capsule or microcapsule and is orallyadministered.

It is to be noted that high purity EPA-E soft capsule (Epadel™ andEpadel S™) are commercially available in Japan as safe therapeuticagents for arteriosclerosis obliterans and hyperlipidemia with reducedside effects, and the proportion of EPA-E in the total fatty acid is atleast 96.5% by weight. Further, soft capsule (Omacor™, Ross products)containing about 46% by weight of EPA-E and about 38% by weight of DHA-Eis commercially available in the U.S. and other countries as atherapeutic agent for hypertriglyceridemia. These drugs may be purchasedfor use in the present invention.

The amount and period for administration of the composition forpreventing onset and/or recurrence of the cardiovascular events of thepresent invention should be sufficient for the expression of theintended action and may be adequately adjusted depending on the dosageform, administration route, frequency, severity of the symptoms, bodyweight, age, and the like. When orally administered, the composition maybe administered at an amount of 0.3 to 6 g/day, preferably 0.9 to 3.6g/day, and more preferably 1.8 to 2.7 g/day in terms of EPA-E, and whilethe composition is typically administered in 3 doses, the total amountmay optionally be administered in a single dose or in a few doses. Thecomposition is preferably administered during or after the meal, andmore preferably, immediately (within 30 minutes) after the meal. Whensuch an amount of the composition is orally administered, theadministration period is typically at least one year, preferably atleast two years, more preferably at least three years and a half, andfurther more preferably at least five years. The administration ispreferably continued as long as there is a considerable risk of onsetand/or recurrence of the cardiovascular events. If necessary, drugholidays of about one day to three months, and preferably about one weekto one month may be given.

The HMG-CoA RI that is used in combination with the compositionaccording to the first to fifth embodiments of the present invention ispreferably used according to the recommended administration procedureand the drug type, and the dosage form, administration method, frequencyper day may be adequately adjusted depending on severity of thesymptoms, body weight, sex, age, and the like. When orally administered,the HMG-CoA RI is typically administered 1 or two times per day at 0.05to 200 mg/day, and preferably 0.1 to 100 mg/day, and the total amountmay optionally be administered in a few doses. The amount may be reducedaccording to the administration amount of EPA-E.

It is to be noted that pravastatin sodium (Mevalotin™ tablets and finegranules, Sankyo Co., Ltd.), simvastatin (Lipovas™ tablets, BanyuPharmaceutical Co., Ltd.), fluvastatin sodium (Lochol™ tablets, NovartisPharma K.K. and Tanabe Seiyaku Co., Ltd.), atorvastatin calcium hydrate(Lipitor™ tablets, Astellas Pharma Inc. and Pfizer), pitavastatincalcium (Livalo™ tablets, Kowa Company, Ltd. and Sankyo Co., Ltd., androsuvastatin calcium (Crestor™ tablets, AstraZeneca K.K. and Shionogi &Co., Ltd.) are commercially available in Japan as drugs for treatinghyperlipidemia, and lovastatin (Mevacor™ tablets, Merck) is commerciallyavailable in the U.S. as a drug for treating hyperlipidemia. These drugsmay be purchased and used according to the directions recommended by themanufacturer. Optionally, at least two of these drugs can be combinedand used together.

The preferable daily amount are, for example, 5-60 mg or preferably10-20 mg for pravastatin sodium, 2.5-60 mg or preferably 5-20 mg forsimvastatin, 10-180 mg or preferably 20-60 mg for fluvastatin sodium,5-120 mg or preferably 10-40 mg for atorvastatin calcium hydrate, 0.5-12mg or preferably 1-4 mg for pitavastatin calcium, 1.25-60 mg orpreferably 2.5-20 mg for rosuvastatin calcium, 5-160 mg or preferably10-80 mg for lovastatin, and 0.075-0.9 mg or preferably 0.15-0.3 mg forcervastatin but not limited to them.

The compound of the first to fifth embodiments is used in combinationwith at least one appropriately selected, according to the condition ofthe patient, from a group including anti-platelet drugs such as Aspirin,Ticlopidin, clopidogrel, and cilostazol; anticoagulation drugs such aswarfarin, heparin, and ximelagatran; angiotensin ii receptor competitorsuch as candesartan, and losartan; andiotensin-converting enzymeinhibitor; calcium channel competitor such as amlodipin and cilnidipin;antihypertensive such as α1 blocker; α glucosidase inhibitor such asvoglibose and akarbose; biganide group; thiazolidindion-type such aspioglitazone, rosiglitazone, and riboglitazone; diabetic agent orglucose tolerance improving drug such as quick-acting insulin secretingsecretagogue (e.g., mitiglinide and nateglinide); and antihyperlipidemicdrug such as HMG-CoA RI (described above), fibrate drug, squalenesynthetase inhibitor (e.g., tak-475), cholesterol absorption inhibitor(e.g., ezetimibe).

The composition according to the first to fifth embodiments of thepresent invention can be used in a package in combination with at leastone drug such as HMG-CoA RI and others.

EXAMPLES

Next, the effects of the present composition are shown with Experimentsand Examples, which by no means limit the scope of the presentinvention.

Experiment 1 (Long Term Preventive Action of EPA-E on the Onset ofCardiovascular Events) Test Procedure

A five-year long term observation of onset and/or recurrence of thecardiovascular events was conducted by administering EPA-E tohyperlipidemia patients exhibiting a serum T-Cho concentration of 250mg/dl or higher, including males at the age of 40 to 75 andpostmenopausal females at the age of 75 or younger. The observation wasconducted by a large scale randomized unblinded controlled trial of theEPA-E group (9,326 cases) and the control group (9,319 cases). Thepatients were randomized into the groups at the beginning of the trialso that no significant difference is found between the groups in thebackground factors of the patients, namely, age, sex ratio, history andcomplication, type and proportion of the HMG-CoA RI, serum lipidconcentration, and the like. The patients of both groups were undernutritional counseling, and HMG-CoA RI was administered to them as abase drug.

The data was collected from 18,465 participant patients by about 4,900participant physicians in about 2,900 participant facilities withsufficient case number, randomization, and the strictness required forthe controlled trial. For example, in choosing the participant patients,the serum T-Cho concentration was measured twice at an interval of twoto four weeks except for the cases where the patients underwent anadequate nutritional consulting with high compliance and the cases wherethe fasting blood was collected after cessation of the antilipidemicdrug, in which the measurement was conducted only once. While untreatedpatients were preferable, in the case of patients who had been taking anantilipidemic drug for more than six months at the start of the trial,four weeks of drug holidays (eight weeks in the case of probucol) weregiven. Patients who were administered with the antilipidemic drug forsix months or less at the start of the trial were admitted in the trialwith no drug holiday, and when the drug was HMG-CoA RI, itsadministration was continued while other drugs were changed to HMG-CoARI.

In order to exclude cardiovascular events in the unstable period afterthe onset of myocardial infarction and cardiovascular events such asrestenosis in the unstable period which is conceived to be caused by theangioplasty itself, the patients at or within six months after the acutemyocardial infarction and patients at or within six months after thecardiovascular angioplasty were excluded from the trial subjects, andonly patients who are beyond six months after such events and who areconceived to be in the stable period were included in the trial. Inaddition, patients who are inadequate for the examination of the actionof preventing the onset of cardiovascular events for a long time whichis the object of this trial, for example, patients of unstable anginapectoris, patients with history or complication of serious heartdiseases (such as severe arrhythmia, heart failure, cardiomyopathy,valvular disease, and congenital heart disease), patients at or withinsix months from the onset of cerebrovascular disorder, and patients withcomplication of serious liver disease or kidney disease, as well as thepatients whose participation was judged to be inappropriate by theattending physician were excluded from the trial.

Epadel (Mochida Pharmaceutical Co., Ltd.) was orally administered asEPA-E typically at an adult dose of 600 mg after the meal three times aday. In the case of abnormal serum TG, however, the dose could beincreased to 900 mg per administration and three times a day.

Pravastatin sodium (Mevalotin tablets and fine granules, Sankyo Co.,Ltd.), simvastatin (Lipovas tablets, Banyu Pharmaceutical Co., Ltd.), oratorvastatin calcium hydrate (Lipitor tablets, Astellas Pharma Inc. andPfizer) was used for the HMG-CoA RI, and these drugs were orallyadministered according to the predetermined dosage regimen.

For five years from before the start of the trial to the end of thetrial, the concentration of the serum lipid (T-Cho, HDL-Cho, and TG) wasperiodically measured, and LDL-Cho was calculated by the equation ofT-Cho-HDL-Cho-(TG/5). In addition, onset of cardiovascular events(cardiovascular death (fatal myocardial infarction and sudden cardiacdeath), nonfatal myocardial infarction, cardiovascular angioplasty, newonset of rest angina or effort angina, and destabilization of anginapectoris (hospitalization and cardiovascular angioplasty)) was observed.

It is to be noted that this trial was consistent with “Good PostMarketing Surveillance Practice (GPMSP)” and “Good Clinical Practice(GCP),” and was conducted under trial organization with a trialdirector. Before the trial was started, the content of the trial wasexplained to the patients, and the patients participated in the trial ontheir own free will with informed consent.

Results

In the observation period of five years, the serum T-Cho, LDL-Cho, andTG concentrations decreased in both groups, and no significant change inthe serum HDL-Cho concentration was noted. In particular, decrease inthe serum TG concentration was more significant in the EPA-E group.

The number of incidence and incidence rate (%) of the cardiovascularevents, and the odds ratio calculated for the EPA-E group in relation tothe control group in the observation period of five years are shown inTable 1. The odds ratio was calculated by the equation of (incidencerate of the EPA-E group)/(incidence rate of the control group), and theinhibition rate of onset of the cardiovascular events was calculated bythe equation of {(incidence rate of the cardiovascular events of thecontrol group-incidence rate of the cardiovascular events of the EPA-Egroup)/incidence rate of the cardiovascular events of the controlgroup}×100.

TABLE 1 Control group EPA-E group Cases with the Cases with the Patientgroups cardiovascular cardiovascular categorized by events/all casesevents/all cases Odds background factor (incidence rate, %) (incidencerate, %) ratio All Cases 324/9,319 262/9,326 0.808 (3.48) (2.81)Myocardial No 223/8,817 180/8,778 0.811 Infarction (2.53) (2.05) Yes101/502   82/548  0.744  (20.12)  (14.96) Cardiovascular No 215/8,813185/8,793 0.862 angioplasty (2.44) (2.10) Yes 109/506   77/533  0.671 (21.54)  (14.45)

As a result of EPA-E administration, the incidence rate of thecardiovascular events over five years in relation to all cases reducedto 2.81% compared to the incidence rate of the cardiovascular events inthe control group of 3.48%. The odds ratio was 0.808, and the EPA-Eadministration reduced the incidence rate of the cardiovascular eventsby about 19% compared to the control group.

Accordingly, the effect of preventing onset and/or recurrence of thecardiovascular events by the EPA-E administration was demonstrated.

In the cases of the patients with history of myocardial infarction andthe patients with history of cardiovascular angioplasty, the incidencerates of the cardiovascular events in the control group were 20.12% and21.54%, respectively, and the incidence rates of the cardiovascularevents were significantly higher than the incidence rates of thecardiovascular events in the patients with no history of myocardialinfarction and the patients with no history of cardiovascularangioplasty which were 2.53% and 2.44%, respectively. In the meanwhile,as a result of the EPA-E administration, the odds ratio was 0.744 in thepatients with history of myocardial infarction and 0.671 in the patientswith history of cardiovascular angioplasty, which were significantlylower than 0.811 in the patients with no history of myocardialinfarction and 0.862 in the patients with no history of cardiovascularangioplasty; and accordingly, the EPA-E administration resulted in thedecrease of the incidence rate of the cardiovascular events by about 26%in the patients with history of myocardial infarction and about 33% inthe patients with history of cardiovascular angioplasty compared to thecontrol group.

From the results as described above, the significant effect of the EPA-Eadministration in preventing onset of the cardiovascular events wasdemonstrated for the patients with history of myocardial infarction andthe patients with history of cardiovascular angioplasty.

INDUSTRIAL APPLICABILITY

The composition of the present invention which contains EPA-E, orcontains at least EPA-E as its effective component, is useful inpreventing onset and/or recurrence of the cardiovascular events. Inparticular, the composition and/or method of the present invention isuseful in preventing onset and/or recurrence of the cardiovascularevents of hyperlipidemia patients or hyperlipidemia patients who havebeen treated with HMG-CoA RI.

The composition and/or methods of the present invention is expected toprevent onset and/or recurrence of the cardiovascular events of patientswho have escaped the unstable period after cardiovascular angioplasty.

When the composition of the present invention is used in combinationwith an HMG-CoA RI, the action is further synergistically enhanced, andsuch a use is expected to further improve the effect for preventingonset and/or recurrence of the cardiovascular events in patients whohave experienced the cardiovascular events, especially patients beyondsix months after the cardiovascular angioplasty. Accordingly, such useof the present composition with the HMG-CoA RI is clinically favorable.

1. A method for preventing onset and/or recurrence of cardiovascularevents in a patient who has escaped the unstable period aftercardiovascular angioplasty, comprising starting to administer acomposition to the patient after the patient has escaped the unstableperiod, wherein said composition contains ethyl icosapentate as aneffective component; and wherein the proportion of the ethylicosapentate in the total content of fatty acids or derivatives thereofis 96.5% by weight or more.
 2. A method for preventing onset and/orrecurrence of cardiovascular events in a patient after six months havepassed since cardiovascular angioplasty, comprising starting toadminister a composition to the patient after six months have passedsince the cardiovascular angioplasty, wherein said composition containsethyl icosapentate as an effective component; and wherein the proportionof the ethyl icosapentate in the total content of fatty acids orderivatives thereof is 96.5% by weight or more.
 3. The method accordingto claim 1, wherein the patient suffers from hyperlipidemia.
 4. Themethod according to claim 1, wherein the amount of ethyl icosapentate inthe composition is orally administered at an amount of 0.3 g/day to 10.0g/day.
 5. The method according to claim 1, wherein the cardiovascularevent is selected from the group consisting of death, myocardialinfarction, cardiovascular angioplasty, new onset of rest angina, newonset of effort angina, and destabilization of angina pectoris.
 6. Themethod according to claim 1, wherein said composition further containsother fatty acids or derivatives thereof.
 7. The method according toclaim 1, wherein the cardiovascular angioplasty is selected from thegroup consisting of percutaneous transluminal coronary angioplasty(PTCA), percutaneous transluminal coronary recanalization (PTCR),directional coronary atherectomy (DCA), coronary stent implantation(coronary artery stenting), and coronary artery bypass grafting (ACbypass grafting).
 8. The method of claim 1, wherein said patient hasreceived percutaneous transluminal coronary angioplasty (PTCA).
 9. Themethod according to claim 1, wherein the composition starts to beadministered to the patient later than six months after thecardiovascular angioplasty.
 10. The method according to claim 1, whereinthe composition is administered to the patient for at least one year.11. The method according to claim 1, wherein the composition isadministered to the patient for at least two years.
 12. The methodaccording to claim 4, wherein the amount of ethyl icosapentate in thecomposition is orally administered at an amount of 0.9 to 3.6 g/day. 13.The method according to claim 4, wherein the amount of ethylicosapentate in the composition is orally administered at an amount of1.8 to 2.7 g/day.
 14. The method according to claim 1, wherein thecardiovascular event is not restenosis.
 15. The method according toclaim 2, wherein the hyperlipidemic patient has a serum triglyceride of150 mg/dl or higher.
 16. The method according to claim 1, wherein thecomposition is in the form of a capsule.
 17. A method for reducing theincidence rate of a cardiovascular event in a group of patients who haveescaped the unstable period after cardiovascular angioplasty, comprisingstarting to administer a composition to the patient after the patienthas escaped the unstable period, wherein said composition comprisesethyl icosapentate as an effective component; and wherein the proportionof the ethyl icosapentate in the total content of fatty acids orderivatives thereof is 96.5% by weight or more.
 18. A method forreducing risk of onset and/or recurrence of cardiovascular events in apatient who has escaped the unstable period after cardiovascularangioplasty, comprising starting to administer a composition to thepatient after the patient has escaped the unstable period, wherein saidcomposition contains ethyl icosapentate as an effective component; andwherein the proportion of the ethyl icosapentate in the total content offatty acids or derivatives thereof is 96.5% by weight or more.
 19. Amethod for reducing risk of onset and/or recurrence of cardiovascularevents in a patient after six months have passed since cardiovascularangioplasty, comprising starting to administer a composition to thepatient after six months have passed since the cardiovascularangioplasty, wherein said composition contains ethyl icosapentate as aneffective component; and wherein the proportion of the ethylicosapentate in the total content of fatty acids or derivatives thereofis 96.5% by weight or more.